Sunday, December 22, 2024
12/22/2024
The human T-cell leukemia virus type-1 (HTLV-1) is a delta oncoretrovirus that infects and transforms CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive hematological malignancy that is generally resistant to conventional anticancer therapies. The 3' end of the HTLV-1 genome encodes several regulatory proteins (i.e., Tax, Rex, HBZ, p8I, p12I, p13II, and p30II) from a highly- conserved nucleotide sequence, known as pX, which is retained in the majority of ATLL clinical isolates. For nearly four decades, the HTLV-1 has been extensively studied as a general informative model for viral carcinogenesis; however, to date, none of its products have been shown to contain structural or functional similarities to other oncogenic viruses beyond the primate T-cell lymphotropic virus (PTLV) family. My laboratory has identified a core structural domain within the HTLV-1 p30II protein with homology to the E6 oncoproteins of high-risk subtype human papillomaviruses (hrHPVs). Both HTLV-1 p30II and HPV E6 cooperate with the cellular oncoprotein, c-Myc, and prevent p53-dependent apoptosis by inhibiting TIP60-mediated acetylation of the p53 protein on lysine residue K120. Intriguingly, p53 is rarely mutated in HTLV-1+ ATLL and HPV+ cervical cancer clinical isolates –although E6 degrades the p53 protein and significantly reduces its expression through interactions with the ubiquitin ligase, E6AP. Our preliminary studies have demonstrated that the HTLV-1 p30II and HPV16/18 E6 viral oncoproteins induce the expression and mitochondrial localization of the TP53-induced glycolysis and apoptosis regulator (TIGAR) and p53-inducible ribonucleotide reductase (p53R2). Primary patient-derived ATLL and HPV+ cervical carcinoma samples contain elevated levels of TIGAR and p53R2 that correlate with oncogenic c-Myc expression. We have further shown that lentiviral-siRNA-knockdown of TIGAR inhibits in vivo tumorigenesis and metastatic disease progression in xenograft models of HTLV-1-induced T-cell lymphoma and HPV-induced squamous cell carcinoma. Based upon these findings, we hypothesize that the unrelated HTLV-1 and high-risk subtype HPVs may have evolved similar strategies to deregulate host oncogenic and pro-survival signaling pathways by targeting p53 functions. The following Specific Aims are proposed for this R15 AREA project: 1) to elucidate the molecular mechanisms by which the HTLV-1 p30II and high-risk HPV E6 oncoproteins modulate p53-regulated pro-survival signals, 2) to determine how TIGAR and p53R2 contribute to the cooperation between HTLV-1 p30II or hrHPV E6 oncoproteins and cellular oncogenes, and 3) to elucidate the roles of these p53-regulated pro-survival signals in HTLV-1 and HPV-induced tumorigenesis in vivo. The proposed studies will yield valuable new insight into the evolutionary relationship between HTLV-1 and other cancer-inducing viruses and advance our understanding of the roles of p53-regulated pro-survival signals in viral carcinogenesis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).